7-45574806-C-G

Variant names:

• chr7-45574806-C-G
• rs770682134
• NM_021116.4:c.263C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021116.4(ADCY1):​c.263C>G​(p.Pro88Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P88L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ADCY1 NM_021116.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.179
• Publications: 0 publications found

Genes affected

ADCY1 (HGNC:232): (adenylate cyclase 1) This gene encodes a member of the of adenylate cyclase gene family that is primarily expressed in the brain. This protein is regulated by calcium/calmodulin concentration and may be involved in brain development. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ADCY1 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 44

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32676902).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021116.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY1	NM_021116.4	MANE Select	c.263C>G	p.Pro88Arg	missense	Exon 1 of 20	NP_066939.1	Q08828
	ADCY1	NM_001281768.2		c.-330-83C>G		intron	N/A	NP_001268697.1	C9J1J0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY1	ENST00000297323.12	TSL:1 MANE Select	c.263C>G	p.Pro88Arg	missense	Exon 1 of 20	ENSP00000297323.7	Q08828
	ADCY1	ENST00000920696.1		c.263C>G	p.Pro88Arg	missense	Exon 1 of 19	ENSP00000590755.1
	ADCY1	ENST00000432715.5	TSL:2	c.-330-83C>G		intron	N/A	ENSP00000392721.1	C9J1J0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436644 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 714224

African (AFR) AF: 0.00 AC: 0 AN: 30654

American (AMR) AF: 0.00 AC: 0 AN: 42832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25334

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37192

South Asian (SAS) AF: 0.00 AC: 0 AN: 83466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4468

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104060

Other (OTH) AF: 0.00 AC: 0 AN: 59318

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.75
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.18
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.23
Sift	Benign	0.34	T
Sift4G	Benign	0.34	T
Polyphen		0.76	P
Vest4		0.31
MutPred		0.34		Gain of methylation at P88 (P = 0.0154)
MVP		0.69
MPC		1.4
ClinPred		0.32	T
GERP RS		2.8
PromoterAI		0.034	Neutral
Varity_R		0.071
gMVP		0.27
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770682134; hg19: chr7-45614405;